The present invention relates to new substituted pyrazole derivatives, processes for their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular disorders.
It has already been disclosed that 1-benzyl-3-(substituted heteroaryl)-fused pyrazole derivatives inhibit platelet aggregation (cf. EP 667 345 A1).
The present invention relates to new substituted pyrazole derivatives of the general formula (I) 
in which
R1 represents a saturated or aromatic 5- or 6-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which can be bonded via a nitrogen atom and which is optionally substituted up to 3 times identically or differently by amino, azido, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which for its part can be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl. alkoxy, alkoxycarbonyl or acylamino each having up to 5 carbon atoms or by a radical of the formula xe2x80x94OR4,
xe2x80x83in which
R4 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula xe2x80x94SiR5R6R7,
xe2x80x83in which
R5, R6 and R7 are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,
and/or is substituted by a radical of the formula 
xe2x80x94S(O)cxe2x80x94NR9R10,
xe2x80x83in which
a, b and bxe2x80x2 are identical or different and denote a number 0, 1, 2 or 3,
R8 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
c denotes a number 1 or 2 and
R9 and R10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which can optionally be substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which for its part can be substituted by halogen, or
xe2x80x83denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or
xe2x80x83denote cycloalkyl having 3 to 7 carbon atoms, or
R9 and R10, together with the nitrogen atom, form a 5- to 7-membered saturated heterocycle which can optionally contain a further oxygen atom or a radical xe2x80x94NR11, in which
xe2x80x83R11 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula 
xe2x80x83or denotes benzyl or phenyl, where the ring systems are optionally substituted by halogen,
R2 and R3, including the double bond, form a 6-membered saturated or aromatic heterocycle having up to 3 heteroatoms from the group consisting of N. S and/or O, which is optionally substituted up to 3 times identically or differently by formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, which for its part can be substituted by hydroxyl, amino. carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
xe2x80x83and/or the heterocycle is optionally substituted by a group of the formula xe2x80x94NR12R13 or xe2x80x94S(O)cxe2x80x2NR9xe2x80x2R10xe2x80x2, in which
R12 and R 13 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or
R12 denotes hydrogen and
R13 denotes formyl
cxe2x80x2, R9xe2x80x2 and R10xe2x80x2 have the meaning of c, R9 and R10 indicated above and are identical to or different from these
and/or the heterocycle is optionally substituted by phenyl which for its part can be substituted up to 2 times identically or differently by halogen or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms
and/or the heterocycle is optionally substituted by a group of the formula xe2x80x94Nxe2x95x90CHxe2x80x94NR14R15, in which
R14 and R15 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
A represents a 5- or 6-membered aromatic or saturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O or phenyl, each of which is optionally substituted up to 3 times identically or differently by amino. mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which for its part can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
xe2x80x83and/or is substituted by a group of the formula xe2x80x94(CO)dxe2x80x94NR16R17,
in which
d denotes a number 0 or 1,
R16 and R17 are identical or different and
denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms,
and their isomeric forms and salts.
The compounds of the general formula (I) according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Phvsiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can also be separated into the stereoisomerically uniform constituents in a known manner.
Heterocycle in the context of the invention, depending on the abovementioned substituents, in general represents a saturated or aromatic 5- or 6-membered heterocycle which can contain up to 3 heteroatoms from the group consisting of S, N and/or O and which in the case of a nitrogen atom can also be bonded via this. Examples which may be mentioned are: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl. pyrazinyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydroturanyl, 12,3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Thiazolyl, furyl, oxazolyl, pyrazolyl triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred.
Preferred compounds of the general formula (I) according to the invention are those
in which
R1 represents pyrimidinyl, pyridazinyl, pyridyl, pyrazinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, 1.2.3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, each of which is optionally substituted up to 3 times identically or differently by amino, formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which for its part can be substituted by hydroxyl, amino, azido, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino each having up to 4 carbon atoms or by a radical of the formula xe2x80x94OR4,
xe2x80x83in which
R4 denotes straight-chain or branched acyl having up to 4 carbon atoms,
xe2x80x83and/or by a radical of the formula 
xe2x80x94S(O)cxe2x80x94NR9R10,
xe2x80x83in which
a, b and bxe2x80x2 are identical or different and denote a number 0, 1, 2 or 3.
R8 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
c denotes a number 1 or 2 and
R9 and R10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 9 carbon atoms, which can optionally be substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or naphthyl or phenyl, which for their part can be substituted by fluorine or chlorine, or denote phenyl or naphthyl, each of which is optionally substituted by fluorine or chlorine, or denote cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or
R9 and R10, together with the nitrogen atom, form a morpholine ring or a radical of the formula 
xe2x80x83in which R11 denotes hydrogen, methyl or a radical of the formula 
xe2x80x83or denotes benzyl or phenyl, where the ring systems are optionally substituted by fluorine or chlorine.
R2 and R3, including the double bond, form a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each of which is optionally substituted up to 3 times identically or differently by formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkylthio or alkoxycarbonyl each having up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, which for its part can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms.
xe2x80x83and/or the abovementioned heterocyclic rings are optionally substituted by a group of the formula xe2x80x94NR12R13 or xe2x80x94S(O)cxe2x80x2NR9xe2x80x2R10xe2x80x2, in which
R12 and R13 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R12 denotes hydrogen and
R12 denotes formyl
cxe2x80x2, R9xe2x80x2 and R10xe2x80x2 have the meaning of c, R9 and R10 indicated above and are identical to or different from these
and/or the abovementioned heterocyclic rings are optionally substituted by phenyl, which for its part can be substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms and/or the abovementioned heterocyclic rings are optionally substituted by a group of the formula 
xe2x80x83in which
R14 and R15 denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
A represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl. pyrimidyl, pyrazinyl, pyridazinyl or pyridyl, each of which is optionally substituted up to 2 times identically or differently by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkoxyacyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which for its part can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,
xe2x80x83and/or by a group of the formula xe2x80x94(CO)dxe2x80x94NR16R17,
xe2x80x83in which
d denotes a number 0 or 1,
R16 and R17 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
and their isomeric forms and salts.
Particularly preferred compounds of the general formula (I) according to the invention are those
in which
R1 represents imidazolyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, isoxazolyl, oxazolyl or thiazolyl, each of which is optionally substituted up to 3 times identically or differently by formyl, fluorine, chlorine, amino, mercaptyl, cyano, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which for its part can be substituted by hydroxyl, carboxyl, amino, azido, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino each having up to 3 carbon atoms,
and/or by a radical of the formula 
xe2x80x94S(O)cxe2x80x94NR9R10,
xe2x80x83in which
a, b and bxe2x80x2 are identical or different and denote a number 0, 1 or 2,
R8 denotes hydrogen or methyl,
c denotes a number 1 or 2 and
R9 and R10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 9 carbon atoms, which can optionally be substituted by phenyl or naphthyl, or
xe2x80x83denote phenyl or naphthyl, each of which is optionally substituted by fluorine or chlorine, or
xe2x80x83denote cyclopropyl or cycloheptyl, or
R9 and R10, together with the nitrogen atom, form a morpholine ring or a radical of the formula 
xe2x80x83in which
xe2x80x83R11 denotes hydrogen, methyl or a radical of the formula 
xe2x80x83or denotes benzyl or phenyl, where the ring systems are optionally substituted by chlorine,
R2 and R3, including the double bond, form a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl ring, each of which is optionally substituted up to 3 times identically or differently by formyl, mercaptyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl each having up to 4 carbon atoms, nitro, cyano, fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms, which for its part can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl. alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
xe2x80x83and/or the heterocyclic rings are optionally substituted by amino, N,N-dimethyl-amino or by a radical of the formula xe2x80x94NHxe2x80x94CHO or xe2x80x94Nxe2x95x90CHxe2x80x94N(CH3)2 and/or by phenyl,
xe2x80x83which for its part can be substituted by a radical of the formula xe2x80x94O(CH3)2xe2x80x94CH3,
A represents tetrahydropyranyl, phenyl, pyrimidyl, thienyl or pyridyl, each of which is optionally substituted up to 2 times identically or differently by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms, which for its part can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
and their isomeric forms and salts.
Very particularly preferred compounds of the general formula (I) according to the invention are those in which
A represents phenyl, pyrimidyl or fluorine-substituted phenyl or pyrimidyl
and their isomeric forms and salts.
Processes for the preparation of the compounds of the general formula (I) according to the invention have additionally been found, characterized in that, depending on the various meanings of the heterocycles mentioned under R2 and R3 above,
[A] compounds of the general formula (II)
R1xe2x80x94Dxe2x80x83xe2x80x83(II)
in which
R1 has the meaning indicated above,
and
D represents radicals of the formula 
xe2x80x83in which
R18 represents C1-C4-alkyl,
are converted by reaction with compounds of the general formula (III)
Axe2x80x94CH2xe2x80x94NHxe2x80x94NH2xe2x80x83xe2x80x83(III)
xe2x80x83in which
A has the meaning indicated above
in inert solvents, if appropriate in the presence of a base, into the compounds of the general formula (IV) or (IVa) 
xe2x80x83in which
A and R1 have the meaning indicated above,
and, in the case of the compounds of the general formula (IVa), then cyclized with carboxylic acids, nitriles, formamides or guanidinium salts,
and, in the case of the compounds of the general formula (IV), then cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines, in the presence of acids and, if appropriate, under microwaves,
or
[B] in the case where R2 and R3 together form a pyrazine ring, compounds of the general formula (IV) are first converted by nitrosation into the compounds of the general formula (V) 
in which
A and R1 have the meaning indicated above,
in a second step, by means of a reduction, the compounds of the general formula (VI) 
xe2x80x83in which
A and R1 have the meaning indicated above,
are prepared
and finally cyclized with 1,2-dicarbonyl compounds, preferably aqueous glyoxal solution,
or
[C] compounds of the general formula (VII) 
in which
A1, R2 and R3 have the meaning indicated above,
and
L represents a radical of the formula xe2x80x94SnR19R20R21, ZnR22, iodine, bromine or triflate,
xe2x80x83in which
R19, R20 and R21 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms,
and
R22 denotes halogen,
are reacted with compounds of the general formula (VIII)
R1xe2x80x94Txe2x80x83xe2x80x83(VIII)
xe2x80x83in which
R1 has the meaning indicated above
and
if L=SnR19R20R21 or ZnR22,
T represents triflate or halogen, preferably bromine,
and
if L=iodine, bromine or triflate,
T represents a radical of the formula SnR19xe2x80x2R20xe2x80x2R21xe2x80x2, ZnR22xe2x80x2 or BR23xe2x80x2R24xe2x80x2,
xe2x80x83in which
R19xe2x80x2, R20xe2x80x2, R21xe2x80x2 and R22xe2x80x2 have the meaning of R19, R20, R21 and R22 indicated above and are identical to or different from these,
R23xe2x80x2 and R24xe2x80x2 are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,
in a palladium-catalysed reaction in inert solvents, if appropriate in the presence of a base, 
in which
R25 denotes (C1-C6)-alkyl which is optionally substituted by halogen,
compounds of the general formula (IX) 
xe2x80x83in which
A, R2 and R3 have the meaning indicated above,
are converted either directly by reaction with the compound of the formula (X) 
xe2x80x83in which
R25 has the meaning indicated above,
in the system NaOCOxe2x80x94CH3/N-methylpyrrolidine
into the compounds of the general formula (Ia) 
xe2x80x83in which
R2, R3 and A and R25 have the meaning indicated above,
and then, by action of potassium hydroxide in methanol, the acetyl group is removed,
or
first by reaction of the compounds of the general formula (IX) with the compound of the formula (X) the compounds of the general formula (XI) 
xe2x80x83in which
xe2x80x83R2, R3, A and R25 have the meaning indicated above,
xe2x80x83are prepared,
xe2x80x83and in a further step by action of potassium hydroxide the hydroxymethyl compounds are prepared,
xe2x80x83and in the case of the groups xe2x80x94S(O)ZcNR9R10 and xe2x80x94S(O)cNR9R10, starting from the unsubstituted compounds of the general formula (I), first reacted with thionyl chloride and in a second step with the appropriate amines
xe2x80x83and, if appropriate, the substituents mentioned under R1, R2, R3 and/or A are varied or introduced according to customary methods, preferably by chlorination, catalytic hydrogenation, reduction, oxidation, removal of protective groups and/or nucleophilic substitution.
The heterocycles mentioned under R2 and R3 can also be introduced by reaction of the appropriately substituted compounds of the general formula (II) according to other known heterocyclic syntheses.
The process according to the invention can be illustrated by way of example by the following reaction scheme: 
Suitable solvents here for the individual steps of the processes are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
Bases employed for the processes according to the invention can in general be inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines (trialkyl(C1-C6)-amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyco[5,4,0]undec-7-ene (DBU). pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as bases alkali metals such as sodium and their hydrides such as sodium hydride. Sodium and potassium carbonate, triethylamine and sodium hydride are preferred.
The base is employed in an amount from 1 mol to 5 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (II).
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C. preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out at normal, elevated or at reduced pressure (e.g. 0.5 to 5 bar). In general, it is carried out at normal pressure.
Suitable acids for the cyclization are in general protonic acids. These preferably include inorganic acids such as, for example, hydrochloric acid or sulphuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulphonic acids having C1-C4-alkyl radicals or aryl radicals such as, for example, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.
The catalytic hydrogenation can in general be carried out by means of hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenohydrocarbons, or mixtures thereof with catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides or boranes in inert solvents, if appropriate in the presence of a catalyst.
Chlorination is in general carried out using the customary chlorinating agents such as, for example, PCl3, PCl5, POCl3 or elemental chlorine. POCl3 is preferred in the context of the invention.
If the radicals of the formulae xe2x80x94S(O)cNR9R10 and xe2x80x94S(O)cxe2x80x2NR9xe2x80x2R10xe2x80x2 are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. In a further step, the reaction with the amines is carried out in one of the abovementioned ethers, preferably dioxane. If c=2, an oxidation is then carried out according to customary methods. The reactions are carried out in a temperature range from 0xc2x0 C. to 70xc2x0 C. and normal pressure.
The nucleophilic substitutions and Vilsmeier reactions are carried out according to customary, published methods.
The reductions are in general carried out using reducing agents, preferably using those which are suitable for the reduction of carbonyl to hydroxyl compounds. Reduction using metal hydrides or complex metal hydrides in inert solvents is particularly suitable here, if appropriate in the presence of a trialkylborane. Preferably, the reduction is carried out using complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diusobutylaluminium hydride or lithium aluminium hydride. Reduction with dilsobutylaluminium hydride and sodium borohydride is very particularly preferred.
The reducing agent is in general employed in an amount from 1 mol to 6 mol, preferably from 1 mol to 4 mol relative to 1 mol of the compounds to be reduced.
The reduction in general proceeds in a temperature range from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C. in the case of DIBAH, 0xc2x0 C. to room temperature in the case of NaBH4.
The reduction in general proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
The compounds of the general formulae (II) and (III) are known per se or can be prepared by customary methods [cf, for this: J. Hromatha et al., Monatsh. Chem. 1976, 107, 233)
The compounds of the general formulae (IV), (IVa), (V) and (VI) are known in some cases and can be prepared as described above.
Suitable solvents here for process [C] are inert organic solvents which do not chance under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane, halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane is particularly preferred.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C. preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out at normal, elevated or at reduced pressure (e.g. 0.5 to 5 bar). In general, it is carried out at normal pressure.
Suitable palladium compounds in the context of the present invention are in general PdCl2(P(C6H5)3)2, palladium bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenylphosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4, Pd(P(C6H5)3)4 is preferred.
The compounds of the general formula (VIII) are known per se or can be prepared by customary methods.
The compounds of the general formula (VII) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by reacting the compounds of the general formula (XII) 
in which
R2, R3 and A have the meaning indicated above,
L1 represents triflate or halogen, preferably iodine,
with compounds of the general formula (XIII)
(SnR19R20R21)2xe2x80x83xe2x80x83(XIII)
xe2x80x83in which
R19, R20, R21 have the meaning indicated above
as described above with palladium catalysis.
The compounds of the general formulae (XII) and (XIII) are known per se or can be prepared by customary methods.
Process [D] according to the invention is carried out using one of the abovementioned bases, preferably in N-methylpyrrolidone, in a temperature range from 100xc2x0 C. to 200xc2x0 C. preferably at 150xc2x0 C.
The compounds of the general formulae (IX) and (X) are known or can be prepared by customary methods.
The compounds of the general formula (la) and (XI) are new and can be prepared as described above.
In the case in which typical protective groups are employed in the course of derivatization reactions, their removal is in general carried out in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0xc2x0 C. to 70xc2x0 C., preferably at room temperature and normal pressure.
The compounds of the general formula (I) according to the invention show an unforeseeable, valuable spectrum of pharmacological action.
The compounds of the general formula (I) lead to a vasorelaxation/inhibition of platelet aggregation and to a blood pressure fall and also to an increase in the coronary blood flow. These actions are mediated via a direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase. Additionally, the compounds according to the invention increase the action of substances which raise the cGMP level, such as, for example. EDRF (endothelium-derived relaxing factor), NO donors, protoporphvrin IX, arachidonic acid or phenylhydrazine derivatives.
They can therefore be employed in medicaments for the treatment of cardiovascular disorders such as, for example, for the treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarct, stroke, transitory and ischaemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass and also for the treatment of arteriosclerosis and disorders of the urogenital system such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.
The invention moreover includes the combination of the compounds of the general formula (I) according to the invention with organic nitrates and NO donors.
Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the release of NO or NO species. Sodium nitroprusside, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
The invention additionally includes combination with compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are, in particular. inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TiPS 11 p. 150 to 155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect is increased by these inhibitors.
To determine the cardiovascular actions, the following investigations were carried out: in in vitro investigations on cells of vascular origin, the influx on guanylate cyclase-dependent cGMP formation was tested with and without NO donor. The anti-aggregatory properties were shown on human platelets stimulated with collagen. The vasorelaxant action was determined in rabbit aortal rings precontracted with phenylephrine. The hypotentive action was investigated in anaesthetized rats.
Primary endothelial cells were isolated from rabbit aortas by treatment with collagenase soln. The cells were then cultured in culture medium at 37xc2x0 C./5% CO2 until confluence was reached. For the investigations, the cells were passaged, inoculated into 24-hole cell culture plates and subcultured until reaching confluence (xcx9c2xc3x97105 cells/hollow). For the stimulation of endothelial guanylate cyclase, the culture medium was aspirated and the cells were washed once with Ringer solution. After removing the Ringer solution, the cells were incubated for 10 minutes at 37xc2x0 C./5% CO2 in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1 xcexcM). Following this, the test substances (final concentration 1 xcexcM) were added to the cells by pipette and they were incubated for a further 10 minutes. After the end of the incubation time, the buffer solution was aspirated and cold stop buffer at 4xc2x0 C. was added to the cells. The cells were then lysed at xe2x88x9220xc2x0 C. for 16 hours. The supernatants containing the intracellular cGMP were then removed and the cGMP concentration was determined by means of the cGMP-SPA system (Amersham Buchler, Brunswick).
Rabbits are anaesthetized by a blow to the neck and exsanguinated. The aorta is removed, freed from adhering tissue, divided into 1.5 mm wide rings and individually transferred under a pretension into 5 ml organ baths containing warm, carbogen aerated Krebs-Henseleit solution at 37xc2x0 C. of the following composition (mM): NaCl: 119; KCl: 4.8: CaCl2xc3x972 H2O: 1; MgSO4xc3x977 H2O: 1.4; KH2PO4: 1.2; NaHCO3: 25; glucose: 10.
The contractility is detected using Statham UC2 cells, amplified and digitalized by means of A/D converters (DAS-1802 HC, Keithley Instruments Munich), and recorded in parallel on linear recorders. To produce a contraction, phenylephrine is added to the bath cumulatively in increasing concentration.
After several control cycles, the substance to be investigated is investigated in each further passage in increasing dosage in each case and the height of the contraction is compared with the height of the contraction achieved in the last preliminary passage. from this, the concentration is calculated which is necessary in order to reduce the height of the control value by 50% (IC50). The standard administration volume is 5 xcexcl and the proportion of DMSO in the bath solution corresponds to 0.1%.
Male Wistar rats having a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.) After tracheotomy, a catheter is inserted in the femoral artery for blood pressure measurement. The substances to be tested are administered orally in various doses by means of stomach tube as a suspension in Tylose solution.
For determination of the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. As an anticoagulant, 9 parts of blood were admixed to one part of 3.8% strength aqueous sodium citrate solution. By means of centrifugation, platelet-rich citrate plasma (PRP) was obtained from this blood (Jurgens/Beller, Klinische Methoden der Blutgerinnungsanalyse [Clinical Methods of Blood Coagulation Analysis]; Thieme Verlag, Stuttgart, 1959).
For these investigations, 445 xcexcl of PRP and 5 xcexcl of the active compound solution were preincubated at 37xc2x0 C. in a water bath. The platelet aggregation was then determined at 37xc2x0 C. in an aggregometer by the turbidometric method (Born, G. V. R., J. Physiol. (London), 168, 178-195, 1963). For this purpose, the preincubated sample was treated with 50 xcexcl of collagen, an aggregation-inducing agent, and the change in the optical density was determined. For quantitative evaluation, the maximum aggregation response was determined and from this the percentage inhibition compared to the control was calculated.
The compounds described in the present invention are also active compounds for the control of illnesses in the central nervous system which are characterized by disorders of the NO/cGMP system. In particular, they are suitable for the elimination of cognitive deficits, for the improvement of learning and memory power and for the treatment of Alzheimer""s disease. They are also suitable for the treatment of disorders of the central nervous system such as anxiety, tension and depressive states, central nervous system-related sexual dysfunctions and sleep disorders, and also for the regulation of pathological disorders of foodstuff, tea, coffee, alcohl, tobacco and addictive drug intake.
Furthermore, these active compounds are also suitable for the regulation of the cerebral blood circulation and are thus effective agents for the control of migrane.
They are also suitable for the prophylaxis and control of the sequelae of cerebral infarcts (cerebral apoplexy) such as stroke, cerebral ischaemias and craniocerebral trauma. The compounds according to the invention can also be employed for the control of states of pain.
The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically acceptable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, as well as processes for the production of these preparations.
The active compound(s) can optionally be present in one or more of the excipients indicated above and also in microencapsulated form.
The therapeutically active compounds should be present in the abovementioned pharmaceutical preparations in a concentration from approximately 0.1 to 99.5, preferably from approximately 0.5 to 95, % by weight of the total mixture.
In addition to the compounds according to the invention, the abovementioned pharmaceutical preparations can also contain further pharmaceutical active compounds.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound(s) in total amounts from approximately 0.5 to approximately 500, preferably 5 to 100, mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose contains the active compound(s) preferably in amounts from approximately 1 to approximately 80, in particular 3 to 30, mg/kg of body weight.
MeOH=methanol
E=ethanol
EA=ethyl acetate
T=toluene
Ph=phenyl
The numbers after the solvent abbreviations in the following tables under the column Rf denote parts by weight.